Derivative of thiazolo[3,2-a]pyrimidine and a process for the preparation thereof and a drug containing it

ABSTRACT

A derivative of thiazolo [3,2-a] pyrimidine expressed by formula (I) ##STR1## (where R indicates a phenyl group or a benzyl group which has a halogen atom, a lower alkyl or lower alkyloxy group as a substituent group, an alicyclic group or an arylethyl group), and a process for the preparation of a compound of formula (I) comprising cyclizing a compound expressed by formula (II) by application of heat ##STR2## (where a definition of R is as same as that given in case of formula (I) and R&#39; indicates a halogen atom or lower alkyloxy group). A drug which contains this compound as active ingredient is useful for curing autoimmune diseases such as rheumatoid arthritis, nephritis, etc.

TECHNICAL FIELD

The present invention relates to a novel derivative ofthiazolo[3,2-a]pyrimidine, a drug which contains it, and a process forthe preparation of said derivative of thiazolo[3,2-a]pyrimidine. Moreparticularly, the present invention relates to a novel derivative ofthiazolo[3,2-a]pyrimidine having excellent immunoregulating activitieswhich is especially effective in curing such autoimmune diseases asnephritis, rheumatoid arthritis, etc. and a process for the preparationthereof and an immunoregulating drug which contains said derivative asan active ingredient.

BACKGROUND ART

In recent years, immunoregulating therapy has come to be practiced tocure such autoimmune diseases as rheumatoid arthritis, generalized lupuserythematodes, etc. or malignant tumor and a variety of drugs have beendeveloped. As an example of such drugs, the application of levamisole,which is a levorotatory isomer of tetramisole, to the drugs forimmunotherapy of cancer and such autoimmune diseases as rheumatoidarthritis has due attention.

Though it has been reported that levamisole has efficacy in saiddiseases to a certain degree, it has no singularity in its efficacy anddoes not always display its efficacy satisfactorily either. Manyimmunoregulating drugs have been developed but most of them not onlylack singularity in their remedial activities but also raise a problemof side effects, and no satisfactory drugs of this kind are available asyet.

Meanwhile, it is mentioned in the "Journal of American Chemical Society"vol. 64, pp. 2709-2712, 1942, that a derivative of barbituric acid isobtained from 2-aminothiazoline and diethyl malonate, and that thiscompound has a hypnotic action and an anesthetic action as well;however, nothing is mentioned in the journal as to other efficacybesides its hypnotic and anesthetic actions.

The inventors of the present invention have prepared a novelthiazolo[3,2-a]pyrimidine derivative which is a novel barbituric acidderivative different from the derivative of barbituric acid mentioned inthe above journal and made a focused study of the efficacy of this newlyprepared compound. The result is a remarkable finding that it is acompound which has a specific immunoregulating action different from anaction owned by levamisole, or the immunoregulating action based on apharmacological action apart from hypnotic and anesthetic actions, andthat, because of its low toxicity, the abovementionedthiazolo[3,2-a]pyrimidine derivative is very useful for curing suchautoimmune diseases as rheumatoid arthritis, nephritis, etc., thusproducing the present invention.

DISCLOSURE OF INVENTION

The present invention is directed to a derivative ofthiazolo[3,2-a]pyrimidine expressed by the following formula (I)##STR3## (where R indicates a phenyl group or a benzyl group which has ahalogen atom, a lower alkyl or lower alkyloxy group as a substituentgroup, an alicyclic group or an arylethyl group), and a process for thepreparation of the derivative of thiazolo[3,2-a]pyrimidine expressed bythe following formula (I) ##STR4## (where a definition of R is as sameas that given in case of the abovementioned formula (I), comprisingcyclizing a compound expressed by the following formula (II) byapplication of heat ##STR5## (where R indicates a phenyl group or abenzyl group which has a halogen atom, a lower alkyl or lower alkyloxygroup as a substituent group, an alicyclic group or an arylethyl group,and R' indicates a halogen atom or lower alkyloxy group), and animmunoregulating drug which contains the derivative ofthiazolo[3,2-a]pyrimidine expressed by the abovementioned formula (I) asan active ingredient.

BEST MODE OF CARRYING OUT THE INVENTION

R of the derivative of thiazolo[3,2-a]pyrimidine expressed by theaforementioned formula (I) of the present invention is a phenyl group ora benzyl group which has a halogen atom, a lower alkyl or lower alkyloxygroup as a substituent group, an alicyclic group or an arylethyl group.

As a phenyl group or a benzyl group which has a halogen atom, loweralkyl or lower alkyloxy group as a substituent group, there are suchphenyl groups as p-chlorophenyl, o-chlorophenyl, m-chlorophenyl,p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-bromophenyl,m-bromophenyl, o-bromophenyl, etc. which have a halogen atom as asubstituent group; such phenyl groups as p-tolyl, o-tolyl,o-ethylphenyl, m-isopropylphenyl, p-butylphenyl, etc. which have a loweralkyl group as a substituent group; such phenyl groups aso-methoxyphenyl, p-ethoxyphenyl, m-propoxyphenyl, etc. which have alower alkyloxy group as a substituent group; such benzyl groups asp-chlorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-fluorobenzyl,o-fluorobenzyl, m-fluorobenzyl, p-bromobenzyl, m-bromobenzyl,o-bromobenzyl, etc. which have a halogen atom as a substituent group;such benzyl groups as p-methylbenzyl, o-ethylbenzyl, m-isopropylbenzyl,etc. which have a lower alkyl group as a substituent group; and suchbenzyl groups as o-methoxybenzyl, p-ethoxybenzyl, m-propoxybenzyl, etc.which have a lower alkyloxy group as a substituent group.

As an alicyclic group, there are cyclopropyl, cyclobutyl, cyclopentyl,cycloheptyl, cyclohexyl, and 2-methylcyclopropyl.

As an arylethyl group, there are phenethyl group and pyridylethyl group.

Of these groups mentioned above, it is preferable to select R from suchphenyl groups or benzyl groups as p-chlorophenyl, o-chlorophenyl,m-chlorophenyl, p-chlorobenzyl, o-chlorobenzyl, m-chlorobenzyl,p-fluorophenyl, m-fluorophenyl, o-fluorophenyl, p-fluorobenzyl,o-fluorobenzyl, m-fluorobenzyl, p-bromophenyl, m-bromophenyl,o-bromophenyl, p-bromobenzyl, m-bromobenzyl, and o-bromobenzyl whichhave a chlorine atom, fluorine atom, or bromine atom as a substituentgroup respectively, a cyclohexyl group or a phenethyl group.

It is especially preferable to select R from such chlorobenzyl groupsand chlorophenyl groups as p-chlorobenzyl, o-chlorobenzyl,p-chlorophenyl and o-chlorophenyl.

A derivative of thiazolo[3,2-a]pyrimidine of the present invention maybe of enol form and a derivative of enol form has the samepharmacological activity.

Also said derivative may take the form of acid addition salt of aninorganic acid or an organic acid. As an inorganic acid, there arehydrochloric acid, hydrobromic acid, and hydroiodic acid, and as anorganic acid, there are acetic acid, propionic acid, lactic acid, andmaleic acid, for instance.

A derivative of thiazolo[3,2-a]pyrimidine expressed by said formula (I)can be prepared by cyclizing a compound expressed by the followingformula (II) by application of heat ##STR6## (where R indicates a phenylgroup or benzyl group which has a halogen atom, a lower alkyl or loweralkyloxy group as a substituent group, an alicyclic group or anarylethyl group, and R' indicates a halogen atom or lower alkyloxygroup).

R of the above formula (II) is the same R as in the aforementionedformula (I).

R' is a halogen atom such as bromine, iodine, chlorine etc. or a loweralkyloxy group such as methoxy, ethoxy, etc.

The cyclization of a compound expressed by the abovementioned formula(II) by application of heat may be conducted either with the use of asolvent or in the absence of a solvent. In the cyclization in which asolvent is used, toluene, xylene, cumene, cymene, tetralin, decalin,diethylene glycol dimethyl ether, diethylene glycol diethyl ether,diethylene glycol dibutyl ether, diphenyl ether, dimethyl sulfoxide,dimethylformamide, nitrobenzene, etc. may be mentioned as recommendablesolvents. The amount of such solvents to be used is usually in the rangeof 1 to 1,000 times the molar quantity of the material compound.

Though the reaction temperature and time vary depending upon thestarting material, presence or absence of a solvent, kind of thesolvent, the desired derivative of thiazolo[3,2-a]pyrimidine is usuallyobtained by conducting the reaction at 80° to 320° C. for 1 minute to 48hours.

A compound expressed by the aforementioned formula (II) can be obtained,for instance, by making 2-aminothiazoline expressed by the followingformula (III) ##STR7## react with a compound expressed by the followingformula (IV) while heating ##STR8## (where R indicates a phenyl group ora benzyl group which has a halogen atom, a lower alkyl or lower alkyloxygroup as a substituent group, an alicyclic group or an arylethyl group,and R' indicates a halogen atom or lower alkyloxy group).

In the abovementioned formula (IV), R is the same R as defined in theaforementioned formula (I) and R' is the same R' as defined in theaforementioned formula (II).

The abovementioned reaction may be carried out with the use of a solventor no solvent. In case where a solvent is used, the kinds of solventsand their amounts to be used can be the same solvents and amounts asmentioned for cyclizing a compound expressed by the aforementionedformula (II) by heating.

As for the method for the preparation of a derivative ofthiazolo[3,2-a]pyrimidine of the present invention, it is preferablefirst to make a compound expressed by the aforementioned formula (III)react with a compound expressed by the aforementioned formula (IV) whileheating to obtain a compound expressed by the aforementioned formula(II), and, without isolating this compound expressed by formula (II),further let the reaction continue with heating to obtain a derivative ofthiazolo[3,2-a]pyrimidine of the present invention.

A derivative of thiazolo[3,2-a]pyrimidine expressed by said formula (I)is especially used for curing such autoimmune diseases as rheumatoidarthritis, nephritis, etc. and is administered orally, or nonorally byway of the rectum, subcutaneous, muscle, etc.

For oral administration, the drug is prepared in the form of a solidpreparation or a liquid preparation. As a solid preparation, there are atablet, pill, powder, and granule. In preparing these solidpreparations, one or more derivatives of thiazolo[3,2-a]pyrimidine areused as active ingredients and they are mixed with at least one inactivediluent such as commonly used calcium carbonate, potato starch, alginicacid and lactose. The preparation is carried out according to theordinary method and addition agents other than a diluent, for instance,such a lubricant as magnesium stearate may be contained in them.

Liquid preparations for oral administration use contain pharmaceuticallypermissible emulsifier, solvent, suspension, syrup, etc. and commonlyused inactive diluents such as water and liquid paraffin.

These preparations contain other auxiliary agents such as a wettingagent, auxiliary suspending agent, sweetening agent, flavoring agent,aromatic, and preservative in addition to said inactive diluents.

Also these liquid preparations may be enclosed in capsules made fromsuch an assimilable substance as gelatin.

As a solid preparation for rectum administration use, a suppository,which contains one or more active principles and is prepared accordingto a publicly known method, may be mentioned.

Preparations to be administered nonorally include aseptically preparedaqueous and nonaqueous solution, suspension, and emulsion. As solvent orsuspending agent for nonaqueous preparation use, there are propyleneglycol, polyethylene glycol, vegetable oil such as olive oil, andinjectable organic ester such as ethyl oleate. These preparations mayalso contain such auxiliary agents as a preservative, wetting agent,emulsifying agent, and dispersing agent. These preparations can be madeaseptic by filtration through a bacterial filter, or by addition of abactericide, or by irradiation. An aseptic solid preparation preparedbeforehand may be used by dissolving it in aseptic water or asepticinjectionable solvent immediately before its administration.

The dosage of a derivative of thiazolo[3,2-a]pyrimidine is 0.1 to 50mg/Kg, especially preferable in the range of 0.5 to 20 mg/Kg; however,the dosage varies depending upon the condition of the disease and age ofa patient and the method of administration.

The present invention is illustrated for further details but not limitedby the following examples.

EXAMPLE 1

A mixture consisting of 1.0 g of 2-aminothiazoline and 2.4 g ofcyclohexyl diethyl malonate was made to react in a stream of nitrogenfor 30 minutes while heating at 180° C. After the reaction product wasallowed to cool down to room temperature, it was chromatographed on acolumn of silica gel and was developed with ethyl acetate-benzene (1:4)to obtain 2.01 g of desired6-cyclohexyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(yield: 80%). The properties of this matter were as follows:

Melting point: 250° to 251° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3200-2500 (enol form), 1655, 1525, 1426,1321, 705.

NMR (δ_(TMS) ^(DMSO-d6)): 1.0-2.0 (11H, m), 3.50 (2H, t, J=8 Hz), 4.33(2H, t, J=8 Hz), 11.0 (1H, br, D₂ O, disappeared).

EXAMPLE 2

A mixture consisting of 1.02 g of 2-aminothiazoline and 3.0 g ofp-chlorophenyl diethyl malonate was heated at 180° C. for 30 minutes tocarry out the reaction. After the reaction product was allowed to cooldown to room temperature, 30 ml of ether was added thereto, and theprecipitated crystals were filtered off to obtain 1.7 g of desired6-p-chlorophenyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(yield: 63%). The properties of this matter were as follows:

Melting point: 275° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3100-2600 (enol form), 1645, 1590, 1528,1437, 1390.

NMR (δ_(TMS) ^(DMSO-d6)): 3.75 (2H, t, J=8 Hz), 4,43 (2H, t, J=8 Hz),7.4 (4H, m), 11.5 (1H, br).

EXAMPLE 3

A mixture consisting of 1.5 g of 2-aminothiazoline and 4.5 g ofp-chlorobenzyl diethyl malonate was made to react in a stream ofnitrogen for 2 hours while heating at 180° C. 8 ml of diphenyl ether wasadded to the obtained solid reaction product and the mixture was furthermade to react in a stream of nitrogen while heating at 220° C. for 2hours. The product resulting from the reaction was allowed to cool downto room temperature, chromatographed on a column of silica gel andeluted with chloroform-methanol (96:4) to obtain 1.8 g of desired6-p-chlorobenzyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(yield: 38%). The properties of this matter were as follows:

Melting point: 273.5°-275.5° C.

IR (ν_(KBr) ^(max)) cm⁻¹ : 3100-2300 (enol form), 1655, 1640, 1625,1545, 1445, 1403, 1289, 1110, 1098, 800.

NMR (δ_(TMS) ^(DMSO-d6)): 3.48 (br, t, J=8 Hz), 3.52 (s), 4.28 (2H, br,t, J=8 Hz), 7.26 (4H, s), 9.30 (1H, br).

EXAMPLE 4

A mixture consisting of 0.5 g of 2-amino-thiazoline and 1.5 g ofo-chlorobenzyl diethyl malonate was made to react in a stream ofnitrogen for 1.5 hours while heating at 170° C. The reaction productthus obtained was chromatographed on a column of silica gel and elutedwith chloroform-methanol (97-90:3-10) to give 0.86 g of desired6-(o-chlorobenzyl)-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(yield: 45%). The properties of this matter were as follows:

Melting point: 265°-274° C.

IR (ν_(KBr) ^(max)) cm⁻¹ : 3100-2300 (enol form), 1650, 1620, 1528,1440, 1400, 1100, 1038, 748.

NMR (δ_(TMS) ^(DMSO-d6)): 3.52 (t, J=8 Hz), 3.62 (2H, s), 4.33 (2H, t),7.2 (4H, m), 11.63 (1H, br).

EXAMPLE 5

A mixture consisting of 2.0 g of 2-aminothazoline and 5.8 g of phenthyldiethyl malonate was made to react in a stream of nitrogen for 1.5 hourswhile heating at 180° C. 8 ml of diphenyl ether was added to thusobtained oily product and the mixture was again made to react in astream of nitrogen for 1.5 hours while heating at 220° C. The obtainedreaction product was put to column chromatography on silica gel andeluted with chloroform-methanol (90-95:10-5) to give 2.74 g of desired5H-2,3,6,7-tetrahydro-5,7-dioxo-6-phenethylthiazolo[3,2-a]pyrimidine(yield: 51%). The properties of this matter were as follows:

Melting point: 253°-263° C.

IR (ν_(KBr) ^(max)) cm⁻¹ : 3200-2300 (enol form), 1640, 1605, 1515,1400, 1150, 1100, 752.

NMR (δ_(TMS) ^(DMSO-d6)): 2.56 (4H, s), 3.47 (2H, t, J=8 Hz), 4.27 (2H,t, J=8 Hz), 7.20 (5H, s).

EXAMPLE 6

A mixture consisting of 0.5 g of 2-aminothiazoline and 1.3 g ofp-methylbenzyl diethyl malonate was made to react in a stream ofnitrogen for 2 hours while heating at 180° C. The reaction product wasthen put to column chromatography on silica gel and eluted withchloroform-methanol (99:1) to obtain 0.6 g of desired5H-2,3,6,7-tetrahydro-6-p-methylbenzyl-5,7-dioxothiazolo[3,2-a]pyrimidine(yield: 44%). The properties of this matter were as follows:

Melting point: 267°-268.5° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3200-2610 (enol form), 1640, 1615, 1530,1440, 1400, 1287, 1096, 802, 786.

NMR (δ_(TMS) ^(DMSO-d6)): 2.28 (3H, s), 3.53 (2H, s), 3.53 (2H, t, J=8Hz), 4.38 (2H, t, J=8 Hz), 7.28 (4H, s), 10.7 (1H, br).

EXAMPLE 7

5H-2,3,6,7-tetrahydro-6-p-methoxybenzyl-5,7-dioxothiazolo[3,2-a]pyrimidinewas obtained according to the same method as Example 6. The propertiesof this matter were as follows:

Yield: 39%.

Melting point: 228°-230° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3400-2650 (enol form), 1640, 1610, 1530,1505, 1435, 1280, 1240, 1100, 1022, 800.

NMR (δ_(TMS) ^(DMSO-d6)): 3.57 (2H, s), 3.59 (2H, t, J=8 Hz), 3.76 (3H,s), 4.38 (2H, t, J=8 Hz), 6.87 (2H, d, J=9 Hz), 7.27 (2H, d, J=9 Hz),11.3-11.7 (1H, br, D₂ O, disappeared).

EXAMPLE 8

5H-2,3,6,7-tetrahydro-6-o-methoxybenzyl-5,7-dioxothiazolo[3,2-a]pyrimidinewas obtained according to the same method as Example 6. The propertiesof this matter were as follows:

Yield: 55%.

Melting point: 259°-260.5° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3400-2570 (enol form), 1653, 1595, 1515,1446, 1345, 1293, 1208, 1090, 777, 758, 742, 722.

NMR (δ_(TMS) ^(DMSO-d6)): 3.56 (2H, t, J=8 Hz), 3.61 (2H, s), 3.88 (3H,s), 4.40 (2H, t, J=8 Hz), 6.7-7.5 (4H, m), 11.0 (1H, br).

EXAMPLE 9

6-p-fluorobenzyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidinewas obtained according to the same method as Example 6. The propertiesof this matter were as follows:

Yield: 58%

Melting point: 267°-268° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3500-2630 (enol form), 1625, 1540, 1500,1442, 1405, 1287, 1212, 1105, 820, 790, 737.

NMR (δ_(TMS) ^(DMSO-d6)): 3.54 (2H, t, J=8 Hz), 3.59 (2H, s), 4.37 (2H,t, J=8 Hz), 6.9-7.6 (4H, m), 11.5-11.9 (1H, br, D₂ O, disappeared).

EXAMPLE 10

5H-2,3,6,7-tetrahydro-6-p-methoxyphenyl-5,7-dioxothiazolo[3,2-a]pyrimidinewas obtained according to the same method as Example 6. The propertiesof this matter were as follows:

Yield: 18%.

Melting point: 266°-268° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3400-2650 (enol form), 1642, 1600, 1570,1555, 1425, 1395, 1290, 1245, 1180, 1138, 1062, 1028, 952, 860, 835,821, 776, 742.

NMR (δ_(TMS) ^(DMSO-d6)): 3.55 (2H, t, J=7 Hz), 3.75 (3H, s), 4.35 (2H,t, J=7 Hz), 6.7-7.6 (4H, m), 11.3-11.7 (1H, br, D₂ O, disappeared).

EXAMPLE 11

5H-2,3,6,7-tetrahydro-6-O-methoxyphenyl-5,7-dioxothiazolo[3,2-a]pyrimidinewas obtained according to the same method as Example 6. The propertiesof this matter were as follows:

Yield: 27%.

Melting point: 256°-258° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3400-3100 (enol form), 1620, 1592, 1510,1400, 1275, 1140, 1110, 1060, 1045, 1023, 790, 747.

NMR (δ_(TMS) ^(DMSO-d6)): 3.54 (2H, t, J=7 Hz), 3.68 (3H, s), 4.35 (2H,t, J=7 Hz), 6.9-7.5 (4H, m), 10.6 (1H, br).

EXAMPLE 12

5-H-2,3,6,7-tetrahydro-5,7-dioxo6-p-bromophenylthiazolo[3,2-a]pyrimidine was obtained according to thesame method as Example 6, having the following properties:

Yield: 48%.

Melting point: 284°-287° C.

IR (ν_(max) ^(KBr)) cm⁻¹ : 3200-2200 (enol form), 1640, 1540, 1430,1380, 1300, 1225, 1138, 1058, 1008, 950, 825.

NMR (δ_(TMS) ^(DMSO-d6)): 3.55 (2H, t, J=8 Hz), 4.35 (2H, t, J=8 Hz),7.50 (4H, s), 10.5 (1H, br).

EXAMPLE 13

In this example the immunoregulating actions of the undermentionedcompounds obtained in Examples 1 to 5 and Example 9 were examined withthe results shown herein:

6-cyclohexyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(hereinafter referred to as medicine A),6-p-chlorophenyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(hereinafter referred to as medicine B),6-p-chlorobenzyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(hereinafter referred to as medicine C),6-(o-chlorobenzyl)-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(hereinafter referred to as medicine D),5H-2,3,6,7-tetrahydro-5,7-dioxo-6-phenethylthiazolo[3,2-a]pyrimidine(hereinafter referred to as medicine E), and6-p-fluorobenzyl-5H-2,3,6,7-tetrahydro-5,7-dioxothiazolo[3,2-a]pyrimidine(hereinafter referred to as medicine F).

(i) Effect on delayed-type hypersensitivity:

The effect of the medicines was estimated with an index of delayed-typehypersensitivity which is caused by injecting red sheep blood cells asantigen into the pads of mice (see the method described by P. H.Lagrange, G. B. Mackaness, and T. E. Mille, Journal of ExperimentalMedicine, Vol.139, pp.1529-1539, 1974; Immunology, Vol.34, p.363,1978).

Groups consisting of 4 or 5 C3H/He male mice (7 weeks old) were used inthe experiments. The mice were sensitized by injecting 10⁶ red sheepblood cells suspended in 0.2 ml of physiological saline intraveneouslyinto the tail vein. Then the mice were administered orally with theabovementioned medicines in doses mentioned in Table 1 immediately afterthe sensitization, 1 day after the sensitization, 2 days after thesensitization, and 3 days after the sensitization respectively. 24 hoursafter the oral administration of the medicines made 3 days after thesensitization, 10⁸ sheep red blood cells suspended in 25 μl ofphysiological saline were injected subcutaneously dermically into theright hind foot pad of the mice to induce a hypersensitivity. 24 hoursafter the induction of the allergic reaction, the thickness of the padwas measured with a micrometer to determine the increase in thickness(foot pad reaction 0.1 mm) as compared with the thickness of the padbefore the subcutaneous injection of 10⁸ sheep red blood cells thus toknow the effect of the medicines on the delayed-type hypersensitivity.

For the purpose of comparison, experiments were conducted with the micewhich were not given the medicines and with those which wereadministered with levamisole and D-penicillamine respectively in theplace of the medicines of the present invention. The results of theseexperiments are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                                 Number    Foot pad                                                   Dose     of        reaction                                   Medicine        (mg/Kg)  cases     (0.1 mm)                                   ______________________________________                                        Experiment                                                                            Control     --       8       3.1 ± 0.5                             1       Medicine C  0.3      4       4.1 ± 0.2                                     "           1        "       4.9 ± 0.5*                                    "           3        5       4.3 ± 0.4                                     "           10       "       4.1 ± 0.7                                     Levamisole  1        "       4.3 ± 0.4                                     "           3        "       4.6 ± 0.3                                     "           10       4       5.1 ± 0.3*                                    D-penicillamine                                                                           1        5       5.0 ± 0.6                                     "           3        "       5.3 ± 0.4**                                   "           10       "       3.7 ± 0.3                             Experiment                                                                            Control              8       4.7 ± 0.7                             2       Medicine C  1        5       7.2 ± 0.5*                                    "           5        "       6.7 ± 0.7                                     "           25       "       6.5 ± 0.4                                     Medicine B  1        4       5.3 ± 0.8                                     "           5        "       5.7 ± 0.5                                     "           25       "       5.7 ± 1.0                                     Medicine D  1        5       6.9 ± 0.9                                     "           5        4       6.9 ± 1.0                                     "           25       5       6.1 ± 1.2                                     Levamisole  1        4       7.6 ± 0.4*                                    "           5        "       5.9 ± 0.3                                     "           25       5       6.8 ± 1.0                             Experiment                                                                            Control              4       4.7 ± 1.1                             3       Medicine A  1        "       6.3 ± 1.0                                     "           10       "       6.2 ± 1.3                                     Medicine E  1        "       4.0 ± 0.8                                     "           10       "       5.8 ± 0.7                             Experiment                                                                            Control              5       3.0 ± 0.1                             4       Meidcine F  1        "       5.7 ± 0.5**                                   "           3        "       3.9 ± 0.4                             ______________________________________                                         *P < 0.05,                                                                    **P < 0.01                                                               

It is evident from Table 1 that the medicines according to the presentinvention are as effective as levamisole and D-penicillamine inincreasing the thickness of the kind foot pad of mice (foot padreaction), in other words, in accelerating the delayed-typehypersensitivity, which proves that the medicines of the presentinvention have a function to enhance the immunizing action.

(ii) Effect on lymphocyte blast cell transformation

(a) The experiments were made according to the method described in theJournal of Immunology, Vol. 122, pp 1-7, 1979 to study the effect of themedicines on the highly exasperated state of immunizing function createdby adding a mitogen, which is a cell proliferating factor, to spleencells obtained from mice to accelerate the cell division.

In the experiments, spleen cells obtained from normal BAL B/c femalemice (7 to 8 weeks old) were suspended in a culture medium (RPMI-1640)containing 5% fetus calf serum (FCS). Then a mitogen (concanavalin A orlipopolysaccharide) and the medicine dissolved in dimethyl sulfoxidewere added to the culture medium of spleen cells (10⁵ /100 (10⁵ /100μl). The cells were incubated in the microculture plate in a 95% air, 5%CO₂ atmosphere at 37° C. After the 3-day incubation was over,3H-thymidine (0.5 μl Ci/20 μl) was added thereto and the incubation wasconducted for another 18 hours. 3H-thymidine incorporated into the cellswas determined with a liquid scintillation counter.

For the purpose of comparison, experiments were conducted likewise withthe cells to which the medicine or mitogen was not added and with thoseto which levamisole and D-penicillamine were added respectively in theplace of the medicines of the present invention. The results of theseexperiments are shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________                    Mitogen (μg/ml)                                                    Concentration Concanavalin A Lipopolysaccharide                       Medicine                                                                              (μg/ml)                                                                            0     0.25   5       10     50                                __________________________________________________________________________    Medicine C                                                                            0       193 ± 17                                                                         4985 ± 802                                                                        22460 ± 2742                                                                       1996 ± 432                                                                        2644 ± 413                             1.0     143 ± 17                                                                         3653 ± 192                                                                        17919 ± 657                                                                        2167 ± 633                                                                        1654 ± 243                             2.5     164 ± 4                                                                          4753 ± 1004                                                                       13686 ± 1260                                                                       1371 ± 198                                                                        1052 ± 82                              5.0     218 ± 40                                                                         4484 ± 876                                                                        8568 ± 2009                                                                        1529 ± 400                                                                        737 ± 312                      Levamisole                                                                            0       687 ± 59                                                                         8835 ± 648                                                                        24733 ± 1043                                                                       4906 ± 320                                                                        4132 ± 508                             10      1377 ± 157                                                                       11780 ± 922                                                                       93325 ± 12561                                                                      15359 ± 2944                                                                      16667 ± 862                            25      3142 ± 388                                                                       20365 ± 1337                                                                      139837 ± 26679                                                                     48044 ± 6048                                                                      62257 ± 1144                           50      3473 ± 126                                                                       24163 ± 1332                                                                      79916 ± 15075                                                                      63961 ± 7405                                                                      69523 ± 4231                   D-penicillamine                                                                       0       687 ± 59                                                                         8835 ± 648                                                                        24733 ± 1043                                                                       4906 ± 320                                                                        4132 ± 508                             1       490 ± 81                                                                         5171 ± 768                                                                        18657 ± 2176                                                                       1672 ± 261                                                                        2670 ± 473                             10      399 ± 26                                                                         4115 ± 559                                                                        21824 ± 565                                                                        1342 ± 266                                                                        1349 ± 176                             25      359 ± 52                                                                         3932 ± 513                                                                        31558 ± 3340                                                                       1446 ± 320                                                                        1515 ± 390                     __________________________________________________________________________

It is apparent from Table 2 that levamisole has a tendency to acceleratethe incorporation of 3H-thymidine in both the case where mitogen is notadded and the case where mitogen added, while medicine C of the presentinvention does not exert much influence on the incorporation of3H-thymidine in the case where mitogen is not added but it has atendency to strongly suppress the incorporation of 3H-thymidine in thecase where mitogen is added. D-penicillamine shows a tendency somewhatsimilar to that of medicine C but is rather weak.

The above fact concludes that levamisole has the immunostimulativeeffect on both cells which have a normal immune activity and cells whichhave an abnormally stimulated immune activity: on the contrary, themedicines of the present invention exercises no influence on the cellswhich have a normal immune activity but has an immunosuppressive effectonly on cells which have an abnormally stimulated immune activity.Therefore, it is confirmed that the medicines of the present inventionare drugs that have a very singular immunoregulative activity.

(b) The experiments were carried out according to the same method as thepreceding (a) with the use of NZB/WF, female mice which were made to bespontaneously attacked with systemic lupus erythematosus. The resultsare shown in Table 3.

                                      TABLE 3                                     __________________________________________________________________________                    Mitogen (μg/ml)                                                    Concentration  Concanavalin A Lipopolysaccharide                      Medicine                                                                              (μg/ml)                                                                            0      0.25   5       10      50                              __________________________________________________________________________    Medicine C                                                                            0       2137 ± 164                                                                        16327 ± 1282                                                                      33411 ± 5150                                                                       20965 ± 1300                                                                       26212 ± 2662                         1.0     1721 ± 364                                                                        12449 ± 1215                                                                      27807 ± 4082                                                                       19319 ± 1386                                                                       22170 ± 1736                         2.5     1478 ± 240                                                                        10498 ± 966                                                                       22191 ± 865                                                                        14828 ± 1829                                                                       14197 ± 2169                         5.0     1433 ± 133                                                                        9291 ± 1064                                                                       19532 ± 115                                                                        15893 ± 2168                                                                       10867 ± 2430                 Levamisole                                                                            0       2880 ± 736                                                                        15925 ± 1788                                                                      32465 ± 2205                                                                       25136 ± 321                                                                        28834 ± 1544                         10      5411 ± 257                                                                        42026 ± 4849                                                                      65800 ± 7832                                                                       56054 ± 3101                                                                       61717 ± 3538                         25      11775 ± 373                                                                       61492 ± 5661                                                                      94057 ± 418                                                                        89072 ± 3024                                                                       127316 ± 12956                       50      18498 ± 3276                                                                      53202 ± 6127                                                                      119202 ± 15483                                                                     109322 ± 9136                                                                      151299 ± 3331                D-penicillamine                                                                       0       2880 ± 736                                                                        15925 ± 1788                                                                      32465 ± 2205                                                                       25136 ± 321                                                                        28834 ± 1544                         1       2923 ± 105                                                                        16999 ± 519                                                                       35597 ± 5483                                                                       22175 ± 2705                                                                       27587 ± 3280                         10      1853 ± 211                                                                        25081 ± 2500                                                                      32047 ± 4296                                                                       16788 ± 1497                                                                       23217 ± 728                          25      1880 ± 648                                                                        29798 ± 178                                                                       37527 ± 4740                                                                       15557 ± 293                                                                        15880 ± 1491                 __________________________________________________________________________

As shown in Table 3, levamisole accelerates the incorporation of3H-thymidine as in the case of the normal mice in the experimentsconducted in (a) disregard of whether mitogen is added or not added tothe spleen cells obtained from the mice made diseased, while medicine Cof the present invention vigorously suppress the 3H-thymidineincorporation when mitogen is added to the spleen cells obtained fromthe mice made diseased and also suppress the 3H-thymidine incorporationwhen mitogen is not added. D-penicillamine also shows a tendencysomewhat similar to that of medicine C but is rather weak.

It is also concluded from the above fact that, different fromlevamisole, medicine C of the present invention has a specific effect tosuppress the abnormally accelerated immunogenic action of the cells.Thus it is confirmed that the medicines of the present invention has avery singular immunoregulative activity.

From the preceding (i) and (ii), it is evident that the medicines of thepresent invention have such singular immunoregulative activities as toaccelerate the immunity, to exercise no influence to the cells whichhave a normal immunizing function, and to suppress the abnormallyaccelerated immunity.

EXAMPLE 14

This example shows that the medicines of the present invention have thelow toxicity.

The acute toxicity of the medicine was determined by use of groups of 6male ICR mice, 6 weeks old, according to an ordinary method.

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Medicine      Administration                                                                              L D50 (g/Kg)                                      ______________________________________                                        6-p-chlorobenzyl-                                                                           Oral          4 or more                                         5H--2,3,6,7-tetrahydro-                                                                     administration                                                  5,7-dioxothiazolo                                                             [3,2-a] pyrimidine                                                            ______________________________________                                    

It is apparent from Table 4 that the toxicity of the medicines of thepresent invention is very low.

EXAMPLE 15

Tablets consisting of the following components per tablet were prepared:

    ______________________________________                                        Active ingredient (6-p-chlorobenzyl-                                                                   200    mg                                            5H--2,3,6,7-tetrahydro-5,7-                                                   dioxothiazolo [3,2-a]                                                         pyrimidine)                                                                   Lactose                  280    mg                                            Potato starch            80     mg                                            Polyvinyl pyrrolidone    11     mg                                            Magnesium stearate       5      mg                                            ______________________________________                                    

A mixture of the active ingredient, lactose and potato starch washomogeneously moistured with 20% ethanol solution of polyvinylpyrrolidone, sieved through a 2.0 mm mesh sieve, dried at 45° C., andsieved again through a 1.5 mm mesh sieve. The granules thus obtainedwere mixed with magnesium stearate and compressed to give tablets.

The compound obtained in Example 3 was used as an active ingredient torepresent the medicines of the present invention.

EXAMPLE 16

Hara gelatin capsules consisting of the following components per capsulewere prepared:

    ______________________________________                                        Active ingredient (6-p-chlorobenzyl-                                                                   200    mg                                            5H--2,3,6,7-tetrahydro-5,7-                                                   dioxothiazolo [3,2-a]                                                         pyrimidine)                                                                   Micro-crystalline cellulose                                                                            195    mg                                            Amorphous silicic acid   5      mg                                            ______________________________________                                    

The finely powdered active ingredient, microcrystalline cellulose anduncompressed amorphous silicic acid were mixed thoroughly and containedin hard gelatin capsules.

EXAMPLE 17

5 ml ampules consisting of the following components per capsule wereprepared:

    ______________________________________                                        Active ingredient (6-p-chlorobenzyl-                                                                   200    mg                                            5H--2,3,6,7-tetrahydro-5,7-                                                   dioxothiazolo [3,2-a] pyrimidine)                                             Polyethylene glycol 600  200    mg                                            Distilled water   To make a total of                                                                   5.0    ml                                            ______________________________________                                    

Polyethylene glycol and the active ingredient were dissolved in water inan atmosphere of nitrogen, boiled, cooled in an atmosphere of nitrogen,and distilled. Pre-treated water was added to thus obtained solution tomake a prescribed volume and filtered under the aseptic conditions. Thepreparation was conducted in the diffused light.

The filling up was conducted in a stream of nitrogen and thesterilization was carried out at 121° C. for 20 minutes.

INDUSTRIAL APPLICATION

Since the derivatives of thiazolo[3,2-a]pyrimidine of the presentinvention have singular and excellent immunoregulating activities, theycan be used for curing such autoimmune diseases as rheumatoid arthritis,systemic lupus erythematodes, nephritis, nephrosis, Behcet disease,Chrohn disease, idiopathic ulcerative colitis, polyneuritis, fibrosis ofthe lung, autoimmune hemolytic anemia, uveitis, etc.

We claim:
 1. A thiazolo[3,2-a]pyrimidine compound expressed by thefollowing formula (I) ##STR9## where R represents a phenyl group or abenzyl group which has a halogen atom, a lower alkyl group or a loweralkyloxy group as a substituent group, an alicyclic group of 3 to 7carbon atoms, or a phenethyl group.
 2. A thiazolo[3,2-a]pyrimidinecompound according to claim 1, wherein R in the above-mentioned formula(I) is a phenyl group, a benzyl group which has a chlorine atom, afluorine atom or a bromine atom as a substituent group, a cyclohexylgroup or a phenethyl group.
 3. A thiazolo[3,2-a]pyrimidine compoundaccording to claim 1, wherein R in the above-mentioned formula (I) is achlorobenzyl group or a chlorophenyl group.
 4. A process for thepreparation of a thiazolo[3,2-a]pyrimidine compound expressed by thefollowing formula (I) ##STR10## where R represents a phenyl group orbenzyl group which has a halogen atom, a lower alkyl or lower alkyloxygroup as a substituent group, an alicyclic group of 3 to 7 carbon atoms,or a phenethyl group, comprising cyclizing a compound expressed by thefollowing formula (II) by application of heat ##STR11## where thedefinition of R is the same as that given in the case of theabove-mentioned formula (I) and R' represents a halogen atom or a loweralkyloxy group.
 5. A process for the preparation of athiazolo[3,2-a]pyrimidine compound according to claim 4, wherein R' inthe above-mentioned formula (II) is a methoxy group or an ethoxy group.6. An immunoregulation drug containing an effective amount of athiazolo[3,2-a]pyrimidine compound expressed by the above-mentionedformula (I) of claim 1 as an immunoregulating active ingredient.